CEACAM1: A link between metabolic and cardiovascular diseases

CEACAM1：代谢与心血管疾病之间的联系

• 批准号: 8597957
• 负责人: Sonia M. Najjar
• 金额: $ 36.79万
• 依托单位: UNIVERSITY OF TOLEDO HEALTH SCI CAMPUS
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-01-01 至 2016-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8597957
• 关键词: Ablation; Address; Adipose tissue; Animal Model; Apolipoprotein E; Apolipoproteins B; Arterial Fatty Streak; Atherosclerosis; Automobile Driving; Blood; Blood Vessels; Cardiovascular Diseases; Cattle; Cause of Death; Cell physiology; Cells; Central obesity; Cholesterol; Clinical Research; Data; Development; Diet; Disease; Dyslipidemias; Endothelial Cells; Exhibits; Experimental Models; Eye; Fatty Acids; Functional disorder; Genes; Hepatic; Hepatocyte; Hyperinsulinism; Hyperlipidemia; Incidence; Indium; Individual; Insulin; Insulin Receptor; Insulin Resistance; Intervention; Knockout Mice; LDL Cholesterol Lipoproteins; Link; Lipids; Liver; Low Density Lipoprotein Receptor; Mediating; Membrane; Metabolic Diseases; Metabolic syndrome; Metabolism; Modeling; Mus; Pathogenesis; Pathway interactions; Patients; Phenotype; Phosphorylation; Plasma; Play; Predisposition; Production; Regulation; Reporting; Role; Serum; Signal Transduction; Site; Skeletal Muscle; Testing; Therapeutic; Toxic effect; Triglycerides; United States; Vascular Diseases; Vascular Endothelial Cell; Vascular Endothelial Growth Factor Receptor; Vascular Endothelial Growth Factors; Vascular Permeabilities; Vasodilation; Very low density lipoprotein; Work; atherogenesis; base; carcinoembryonic antigen-related cell adhesion molecules; cell type; endothelial dysfunction; feeding; gain of function; high risk; human NOS3 protein; in vivo; innovation; insulin sensitivity; insulin signaling; lipid biosynthesis; loss of function; mouse model; prevent; response

Individuals with metabolic diseases are at a higher risk of developing atherosclerosis, a leading cause of death in the United States and worldwide. Earlier studies have linked dyslipidemia to the initiation and progression of atherosclerosis. However, recent clinical studies raised concerns about the efficacy of lowering plasma cholesterol levels in the progression of atherosclerosis. Although insulin resistance is associated with increased incidence of cardiovascular disease, whether it leads to atherosclerosis independently of its accompanying dyslipidemia remains unclear, largely because of the lack of a suitable animal model to address this question. The CarcinoEmbryonic Antigen-related Cell Adhesion Molecule-1 (CEACAM1) regulates insulin sensitivity by promoting insulin clearance in liver. Accordingly, global null deletion of Ceacam1 gene impairs hepatic insulin clearance and causes hyperinsulinemia, which in turn, results in systemic insulin resistance. Preliminary data show: (i) that global Cc1-/- null mice develop early atherosclerotic lesions and vascular dysfunction even under normal feeding conditions, and (ii) that this occurs in the absence of hyperlipidemia, despite VLDL/LDL cholesterol levels that are usually associated with atherosclerosis regression, not development. This unique animal model of atherogenesis with isolated insulin resistance in the absence of hyperlipidemia demonstrates that systemic insulin resistance resulting from hyperinsulinemia leads to vascular dysfunction and atherosclerosis in the absence of hyperlipidemia. Because phosphorylation of CEACAM1 by both insulin and VEGF receptors regulates Akt1 activation of endothelial Nitric Oxide Synthase (eNOS), an essential step in mediating endothelial function, it is reasonable to propose that CEACAM1 is the shared downstream element in VEGF and insulin signaling in endothelial cells, whose inactivation impinges upon both pathways and causes endothelial dysfunction in insulin resistance. To test this hypothesis, the regulatory effect of CEACAM1 on insulin action along the liver/endothelial cell axis will be investigated. Aim 1 examines whether hyperinsulinemia caused by impaired hepatic insulin clearance, alters insulin action in the endothelial cell, and in this cell-nonautonomous fashion, initiates atheroma development. Aim 2 examines whether altered signaling through CEACAM1-dependent pathways disrupts the endothelial cell's response to insulin and VEGF, and in this cell-autonomous fashion, drives endothelial dysfunction and initiates atherosclerosis. To investigate the specific role of hepatic and endothelial cell CEACAM1 in the pathogenesis of atherosclerosis and vascular dysfunction, a newly generated set of unique animal models of loss-of-function and gain-of-function will be used. Answering these questions will delineate new CEACAM1-dependent mechanisms underlying atherosclerosis along the liver/endothelial cell axis, and pinpoint sites of pharmacologic intervention.

患有代谢性疾病的人患动脉粥样硬化的风险较高，这是动脉粥样硬化的主要原因 美国和世界范围内的死亡。早期研究已将血脂异常与起始和发生联系起来。 动脉粥样硬化的进展。然而，最近的临床研究引起了人们对它的功效的担忧。 降低动脉粥样硬化进展中的血浆胆固醇水平。虽然胰岛素抵抗是 与心血管疾病发病率增加相关，是否导致动脉粥样硬化 独立于其伴随的血脂异常仍不清楚，很大程度上是因为缺乏 适合解决这个问题的动物模型。癌胚抗原相关的细胞粘附 Molecule-1 (CEACAM1) 通过促进肝脏中的胰岛素清除来调节胰岛素敏感性。因此， Ceacam1 基因的整体缺失会损害肝脏胰岛素清除率并导致高胰岛素血症， 这反过来又导致全身胰岛素抵抗。初步数据显示： (i) 全局 Cc1-/- 为空 即使在正常喂养下，小鼠也会出现早期动脉粥样硬化病变和血管功能障碍 (ii) 尽管存在 VLDL/LDL 胆固醇，但这种情况发生在没有高脂血症的情况下 通常与动脉粥样硬化的消退有关，而不是与动脉粥样硬化的发展有关。这种独特的动物 在没有高脂血症的情况下，具有孤立的胰岛素抵抗的动脉粥样硬化模型表明 高胰岛素血症引起的全身胰岛素抵抗导致血管功能障碍 在没有高脂血症的情况下发生动脉粥样硬化。因为 CEACAM1 被两种胰岛素磷酸化 VEGF 受体调节 Akt1 激活内皮一氧化氮合酶 (eNOS)，这是一种重要的 介导内皮功能的步骤，因此可以合理地提出 CEACAM1 是共享的 内皮细胞中 VEGF 和胰岛素信号传导的下游元件，其失活 影响这两条途径并导致胰岛素抵抗中的内皮功能障碍。测试 这一假设，CEACAM1 对沿肝/内皮细胞轴的胰岛素作用的调节作用 将被调查。目标 1 检查高胰岛素血症是否由肝胰岛素受损引起 清除，改变内皮细胞中的胰岛素作用，并以这种细胞非自主方式启动 动脉粥样硬化的发展。目标 2 检查是否通过 CEACAM1 依赖性改变信号传导 途径破坏内皮细胞对胰岛素和 VEGF 的反应，并且在这种细胞自主 时尚，导致内皮功能障碍并引发动脉粥样硬化。探究其具体作用 肝细胞和内皮细胞CEACAM1在动脉粥样硬化和血管功能障碍发病机制中的作用， 将使用一套新生成的独特的功能丧失和功能获得动物模型。 回答这些问题将描述新的 CEACAM1 依赖机制 沿肝/内皮细胞轴的动脉粥样硬化，以及药物干预的精确部位。